DNA replication begins in the early S phase. Upon
unwinding of DNA by Minichromosome maintenanceprotein complex (MCM complex) with the help of Origin recognition complex
(ORC complex) and Replication proteins (RPA), the DNA polymerase
alpha/primase is recruited to DNA (see map
Start of DNA replication) [1].

DNA polymerase alpha/primase synthesizes RNA/DNA hybrid
on the newly unwound DNA at ~ 30 nucleotides per initiation. Then DNA
polymerase delta continues synthesis of this fragment. DNA
polymerase delta and DNA polymerase epsilon
are activated by proliferating cell nuclear antigen (PCNA)
with help of the Replication factor C [2].
PCNA is a homotrimer that forms a ring shaped structure.
PCNA binds to the DNA polymerase
delta and DNA polymerase epsilon and acts as
a ?sliding clamp?, preventing the polymerases from falling off the
DNA. Replication factor C is a
member of the AAA+ superfamily proteins; it binds to the 3' end of the primer
and uses ATP to open up the PCNA ring and close it around
the template DNA [3].

Because of the anti-parallel nature of DNA, the two
parental strands are replicated by different mechanisms during the progression of the
replication fork. The parental strand, which is 3' to 5' relative to the direction of
unwinding, can be replicated continuously by a DNA polymerase
alpha/primase and DNA polymerase delta
synthesizing 5' to 3'. This is known as the ?leading strand? [1].

On the other strand (?lagging strand?), however, replication is trickier because DNA
polymerases cannot synthesize DNA in a 3' to 5' direction.
To circumvent this problem, this strand is replicated discontinuously; as the helicase
unwinds DNA, DNA polymerase
alpha/primase and DNA polymerase delta
(and/or DNA polymerase epsilon) synthesize short
oligonucleotides called Okazaki fragments [1].

Thus, the lagging strand is synthesized discontinuously as a series of RNA-DNA hybrid
molecules. Maturation of Okazaki fragments involves removal of the RNA primers (and
perhaps some DNA) by flap endonuclease1 (FEN1). RNA primers
are cleaved by Ribonuclease H1. Maturated Okazaki fragments
are connected by DNA ligase I. Activites of
FEN1 [4] and DNA ligase I
[5] are stimulated by PCNA.

The topology of a DNA molecule changes as it is unwound during DNA replication by
topoisomerases. Topoisomerases are grouped into two types, both of which catalyze the
cleavage and regulation of the DNA with the formation of an intermediate that is
covalently bound to DNA through a phosphotyrosine bond. Topoisomerase I
(TOP1) is monomeric and pass a single-stranded region of DNA
through a break in the opposite strand [1]. WRN
stimulates the ability of TOP I to relax negatively
supercoiled DNA and specifically stimulate the religation step of the relaxation reaction
[6], [7].

Type II topoisomerases (TOP2) are homodimeric or
heterotetrameric and pass a region of double-stranded DNA through a break in a second
duplex DNA molecule (inter- or intramolecularly) [8]. It is show, that
TOP2 may be regulated by tumor suppressor
BRCA1-dependent ubiquitination [9],

Termination occurs when two opposing replication forks meet and the nascent DNA from
the two forks is ligated together. Replication machinery elements must be displaced
before the completion of replication to allow the polymerases to replicate the last bits
of sequence [1].

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